Studies of families with neurofibromatosis type 1 (NF1) have demonstrated that the severity of this disease depends on modifier genes in the individuals. We are using a mouse model of the malignancies associated with NF1 in which the Nf1 and p53 gene are mutated on the same chromosome and screening for modifier genes in different strains of mice. We have recently identified a region responsible for resistance to developing malignant peripheral nerve sheath tumors (MPNSTs) in one strain of mice, and another region responsible for susceptibility to astrocytoma. We are working to identify candidate modifier genes within these regions that can be tested for their role in tumorigenesis in our mouse model and then in human cancers. During fiscal year 2009, we have tested expression and splicing differences in several candidate modifiers affecting MPNSTs and have found strain-specific differences in several. We have demonstrated that both imprinted factors on mouse chromosome 11 and the gender of the mouse alter how modifiers act using chromosome substitution strains (Walrath et al Mammalian Genome 2009). Through these studies we are beginning to build up networks of genetic interactions affecting susceptibility. We have furthermore gathered evidence that an imprinted gene on mouse chromosome 11 acts in a haploinsufficient, tumor suppressive manner when mutated in our model system. Further study of this gene in the upcoming years may elucidate the mechanism of inherited susceptibility/resistance. We are continuing our work to phenotype 600 mice to identify modifier loci affecting resistance to astrocytoma.